The present invention relates to novel benzopyrans having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of hypertension.
European Patent Publication 158,923 discloses classes of chromans that are described as having blood pressure lowering activity.
The present invention discloses compounds represented by formula (I) ##STR1## wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of H, halogen, F, C.sub.1 to C.sub.7 alkyl, C.sub.3 to C.sub.7 cycloalkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C.sub.1 to C.sub.7 alkoxy, C.sub.1 to C.sub.7 alkylcarbonyl, C.sub.3 to C.sub.7 cycloalkylcarbonyl, C.sub.1 to C.sub.7 thio alkyl, C.sub.1 to C.sub.7 sulfoxy alkyl, amino, C.sub.1 to C.sub.7 mono- or disubstituted amino, C.sub.1 to C.sub.7 mono- or disubstituted amido; R.sub.3 is selected from the group consisting of ##STR2## Also disclosed are N-oxides and pharmaceutically acceptable salts thereof.
A preferred aspect of the present invention are compounds of formula (II) ##STR3## wherein R.sub.4 is selected from the group consisting of H, F, trifluoromethoxy, trifluoromethyl, C.sub.1 to C.sub.7 alkoxy, cyano, nitro, C.sub.1 to C.sub.7 alkylcarbonyl or C.sub.3 to C.sub.7 cycloalkylcarbonyl; R.sub.5 is selected from the group consisting of ##STR4## the N-oxides and pharmaceutically acceptable salts thereof.
A further preferred aspect of the present invention are the compounds:
6-[(trans)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-ben zopyran -4-yl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; PA0 (trans)-6-[3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-ben zopyran-4-yl]-5,6dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; PA0 (trans)-2-[3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-ben zopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one; PA0 (trans)-2-[3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-ben zopyran-4-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; PA0 (trans)-6-[3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-ben zopyran-4-yl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one;
and the pharmaceutically acceptable salts thereof.
The compounds of formula (I), are asymmetric and, therefore, can exist in the form of optical isomers. The present invention extends to all such isomers individually and as mixtures, such as racemic modifications.
Preferably, a compound of formula (I) is in substantially pure form.
Examples of compounds of formula (I) include the compounds prepared in the Examples hereinafter.
The present invention also provides a process for the preparation of a compound of formula (I), which is exemplified by the reaction of a compound of formula (V) ##STR5## wherein R.sub.1 and R.sub.2 are as defined hereinbefore with a compound of formula (VI) to (XII) ##STR6##
It is particularly preferred that the reaction between the compounds of formula (V) and (VI) to (XII) is carried out under alkylation conditions so as to facilitate the formation of the desired bonds, for example, by heating in the presence of ZnCl.sub.2.NaCNBH.sub.3 in ethanol.
The compounds of formula (VI) to (XII) can be prepared by the same process for the preparation of the compound of formula (VI) set forth below. ##STR7##
The production of preferred compounds of the present invention is illustrated by Synthetic Process B. ##STR8##
The compounds of formula (I) can be converted to the corresponding N-oxides by treatment with hydrogen peroxide by conventional means.
The compounds of this invention are capable of forming acid addition salts with therapeutically acceptable acids. The acid addition salts are prepared by reacting the base form of the appropriate compound of formula (I) with one or more equivalents, preferably with an excess, of the appropriate acid in an organic solvent, for example diethyl ether or an ethanol diethyl ether mixture.
These salts, when administered to a mammal, possess the same or improved pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the basic compounds. Suitable acids to form these salts include the common mineral acids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids, e.g. ascorbic, citric, lactic, aspartic or tartaric acid; and acids which are sparingly soluble in body fluids and which impart slow-release properties to their respective salts, e.g. pamoic or tannic acid or carboxymethyl cellulose. The preferred salt is the hydrochloride salt. The addition salts thus obtained are the functional equivalent of the parent base compound in respect to their therapeutic use. Hence, these addition salts are included within the scope of this invention and are limited only by the requirement that the acids employed in forming the salts be therapeutically acceptable.
The compounds of formula (V) are novel compounds and can be prepared in accordance with the processes described herein.
The compounds of formula (VI) to (XII) are known compounds or can be prepared by conventional procedures from known compounds.
As mentioned previously, the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of hypertension.
Since the compounds of the present invention are believed to be K.sup.+ channel openers, they could also have utility in the treatment of heart failure; in the treatment of peripheral vascular disease; for hair growth stimulation; and as bronchodialators in the treatment of asthma.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier. In particular, the present invention provides an anti-hypertensive pharmaceutical composition which comprises an antihypertensive effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and .beta.-blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of hypertension.
The present invention further provides a method of treating hypertension in mammals including man, which comprises administering to the afflicted mammal an antihypertensive effective amount of a compound or a pharmaceutical composition of the invention.
The resolution of compounds of formula (I) into optical isomers may be accomplished by reacting the racemate with an optically pure chiral auxiliary, preferable 1-(1-naphthyl)ethyl isocyanate or .alpha.-methylbenzyl isocyanate, to form a mixture of two diastereomers. These diastereomers are then separated by physical means, such as chromatography or crystallization. Each is reacted to remove the chiral auxiliary to afford the enantiomers of compounds of formula (I).
The resolution of compounds of formula (I) into optical isomers may also be accomplished by the resolution process described in Soll et al, AHP-9458, serial number not yet known.